Obesity is a condition in which the natural energy reserve, stored in the fatty tissue of humans and other mammals, is increased to a point where it is associated with certain health conditions or increased mortality. Although obesity is an individual clinical condition, it is increasingly viewed as a serious and growing public health problem, as excessive body weight has been shown as a predisposition to various diseases including cardiovascular diseases, diabetes mellitus type 2, sleep apnea and osteoarthritis. Worldwide, it is estimated that more than 250 million people are obese, and it is a condition that is increasing at an alarming rate. In the US, it is estimated that up to 32% of children may be obese, and experts estimate that up to 50% of the adult population in the US may be obese within a generation.
Conventional treatment for obesity includes dietary modification, and pharmacotherapy for which only three drugs are typically prescribed: phentermine which is a short-term therapy, and orlistat (XENICAL) and sibutramine (MERIDIA/REDUCTIL) which are suitable for long-term treatment. However, pharmacotherapy with these drugs is generally only recommended in obese patients with a BMI>30 kg/m2 or in patients with a lower BMI who have android obesity (an obesity type more commonly associated with serious morbidity and mortality). As such, there is a continuing need to develop new therapeutics for use in the treatment of obesity and related conditions.
In this regard, the hypothalamic melanocortin-4 receptor (MC4-R) is part of a central appetite reducing (anorexigenic) pathway, and it is known that mutations of this receptor can lead to a loss of function and result in severe obesity. MC4-R is a G-protein coupled receptor (GPCR) which has been shown to be expressed primarily in the brain (Gantz et al., 1993, J. Biol. Chem. 268:15174-15179; Mountjoy et al., 1994, Mol. Endo. 8:1298-1308) and is known to play a crucial role in energy balance (Cowley, M A, Eur. J. Pharmacol. 480:3-11, 2003; Elies, R. et al. Eur. J. Biochem. 251:659-666, 1998). The sequences of the MC4-R have been reported in the literature. In this regard, see for example European Patent Application No. 1167386 (canine and feline sequences) and U.S. Pat. Nos. 5,703,220 and 6,117,975 (human sequences). The rat sequence is known to consist of 332 amino acid residues (NCBI Accession No. NP037231).
The MC4-R has been a target of research interest in the treatment of body weight disorders (see, for example, PCT Patent Application Publication No. 97/47316 which discloses drug screening assays for identifying therapeutics useful for such purposes), and non-antibody compounds and polyclonal antibodies that affect the activity of the MC4-R have been reported (see in this regard, for example, U.S. Pat. No. 7,169,777, US Patent Publication No. 2004/0082779, European Patent Application No. 1167386, PCT Publication Nos. WO 01/085930 and 98/10068, and Peter et al., Am. J. Physiol. Regul. Integr. Comp. Physiol. 292:R2151-R2158, 2007). Further, although various methods for detecting/identifying auto-antibodies are known for various diseases and conditions, none are known for obesity (see, in this regard for example, European Patent Nos. 0943098 and EP 145662, PCT Patent Publication No. WO 03/014742, and U.S. Pat. No. 4,690,905).
Accordingly, there exists needs to develop new and improved diagnostic and therapeutic methods and agents for obesity and related conditions, and in particular that involve the MC4-R. It is to these needs that the present invention is directed.